Schistosoma mansoni is a parasitic trematode and responsible for schistosomiasis, a neglected tropical disease that affects more than 250 million people worldwide, primarily in sub-Saharan Africa, South America, and parts of the Middle East (Lo et al., 2022). The parasite’s life cycle involves freshwater snails as intermediate hosts and humans as definitive hosts, where it matures in the mesenteric veins and releases eggs that trigger a robust immune response (McManus et al., 2018). The primary pathological consequence of S. mansoni infection is hepatointestinal schistosomiasis, characterized by chronic liver inflammation, fibrosis, and metabolic disturbances. Schistosomiasis is transmitted in freshwater environments by schistosome larvae (cercariae) that develop within aquatic snails (Figure 1A).

These free-swimming larvae penetrate the skin of individuals who swim or wade in contaminated water. Following skin penetration, cercariae transform into schistosomula, enter the circulation and migrate via the blood and lymphatic vessels to the liver. Within the portal venous system, the parasites mature into adult worms, with male and female worms pairing at this stage. The paired worms subsequently migrate to the venous plexuses of the bladder in Schistosoma haematobium infections or to the intestinal venous plexuses in infections caused by S. mansoni, S. japonicum, and related species. Female worms deposit large numbers of eggs within the small venules of the bladder or intestinal wall, respectively. While a fraction of these eggs traverse surrounding tissues and are excreted—via feces in intestinal schistosomiasis—a substantial proportion become trapped within host tissues, particularly in the portal venous system of the liver. Retained eggs elicit granulomatous inflammation and progressive immune-mediated pathology, ultimately leading to chronic hepatic fibrosis (Schwartz and Fallon, 2018).

The chronic immune response, dominated by a Th2-mediated reaction, leads to fibrosis, hepatomegaly, and portal hypertension (Grzych et al., 1991; Elliott, 1996). Over time, metabolic alterations occur due to the combined effects of inflammation, fibrosis, and changes in immune signaling. Periportal fibrosis is a severe morbidity caused by both current and past exposure to intestinal schistosomes (Ewuzie et al., 2025). Recent data obtained from BALB/c mice indicate that activation of the NLRP3 inflammasome in hepatic sinusoidal stellate cells contributes to Schistosoma japonicum–induced liver fibrosis through NF-κB–dependent signaling pathways. NLRP3 inflammasome activation occurs in both Kupffer cells (KCs) and hepatic stellate cells (HSCs), with a more pronounced effect observed in KCs. It is hypothesized that inflammasome activation in KCs promotes the production of proinflammatory cytokines, such as interleukin-1β (IL-1β), which subsequently activate HSCs, leading to extracellular matrix deposition and the development of liver fibrosis (Zhang et al., 2019). In addition, patients with schistosomiasis exhibit elevated expression of Hedgehog (Hh) ligands compared with healthy individuals. Activated liver sinusoidal endothelial cells (LSECs) and myofibroblasts are responsive to Hedgehog signaling (Pereira et al., 2013). Soluble egg antigens (SEA) stimulate hepatic macrophages to produce Hh ligands, thereby promoting alternative macrophage activation, fibrogenesis, and vascular remodeling during schistosomiasis (Pereira et al., 2013). Praziquantel (PZQ), the most important drug for the treatment of schistosomiasis, is effective and well tolerated against adult worms of all six Schistosoma species that affect humans. However, it does not eliminate the eggs trapped in the liver, nor does it prevent reinfection (Woldegerima et al., 2019), raising concerns about the potential development of drug resistance (Eastham et al., 2024). The liver is a primary target of S. mansoni pathology, experiencing profound metabolic disruptions due to chronic inflammation, fibrosis, and oxidative stress. Sex hormones modulate immune responses and liver metabolism, potentially influencing disease progression and severity (Xu et al., 2022; Sciarra et al., 2023). Male and female hosts may metabolize glucose, lipids, and amino acids differently in response to infection, influencing disease outcomes and treatment efficacy. Understanding these metabolic variations can help identifying individuals at higher risk for severe liver fibrosis, which enables earlier interventions. Incorporating sex-specific metabolic data into disease models might even improve predictions of disease progression and treatment responses, aiding clinical decision-making.

Although few studies have been explicitly designed to examine sex as a biological variable in S. mansoni infection, this article presents some new aspects and summarizes the available results of studies with male and female hosts to highlight possible gender-specific differences. We recognize the methodological limitations inherent in comparing studies with differing objectives and experimental designs. Therefore, we present such comparisons cautiously and transparently, not as definitive evidence but as hypothesis-generating observations that underscore the need for more targeted research. Excluding these studies altogether would risk overlooking meaningful biological signals that could guide future investigations.

This article focuses on the sex-specific effects of S. mansoni infection on liver metabolism. Figure 1 summarizes the infection cycle of S. mansoni and the metabolic interactions of the hepatic parenchyma with trapped Schistosoma eggs.

Gender-specific differences in hepatic schistosomiasis are well-documented, with male gender consistently identified as a risk factor for more severe disease progression (Ahmed and Alharbi, 2025; Zongo et al., 2025). While socio-economic, behavioral, and environmental factors have been suggested to contribute to this disparity, emerging evidence indicates that biological and molecular mechanisms play a pivotal role in shaping disease outcomes (Tavakoli Pirzaman et al., 2024). However, the precise molecular pathways underlying these sex-based differences remain largely unexplored.

In general, the risk of hepatocellular carcinoma (HCC) caused by hepatitis B or hepatitis C is significantly higher in men than in women (Yu and Chuang, 2009). However, with increasing age, the effects of alcohol consumption and viral infections on the development of HCC intensify, while the influence of male gender decreases (Yi et al., 2018). Recent findings from meta-analyses, animal models, and in vitro studies suggest that S. mansoni infection may not only exacerbate liver fibrosis but also predispose individuals to hepatocellular carcinoma (HCC) (Bülow et al., 2021, 2023, 2024). The risk appears to be significantly amplified in the presence of co-infections with hepatitis B virus (HBV) or hepatitis C virus (HCV), which synergistically contribute to chronic liver damage, cirrhosis, and carcinogenesis (Bülow et al., 2021; Allam et al., 2024). In the S. mansoni-infected HCC group, the proportion of women was slightly higher at 25% than in the HCC group without schistosomiasis (19%). Due to the low overall number of HCC cases in women, this finding was not statistically significant (Allam et al., 2024). Women are often infected through domestic activities involving contact with water, such as washing clothes and fetching drinking water (Reitzug et al., 2024). In addition, women and people without schooling are among the disadvantaged members of the community who receive little health education and are therefore exposed to an increased risk of S.mansoni infection (Adoka et al., 2014). Chronic inflammation driven by S. mansoni eggs trapped in hepatic tissue induces a persistent Th2-mediated immune response, oxidative stress, and fibrotic remodeling - all of which are known to create a microenvironment conducive to oncogenic transformation (Härle et al., 2023; Bülow et al., 2024; Russ et al., 2024). Strikingly, gender disparities in HCC incidence among S. mansoni-infected individuals mirror global patterns observed in liver cancer, where men exhibit a significantly higher prevalence than women. A recent study reported a male-to-female ratio of 3:1 (75% vs. 25%) among HCC patients with a history of S. mansoni infection (Allam et al., 2024). This pronounced inequality justify the assumption that sex hormones, differential immune responses and metabolic differences might influence the course of the disease. Testosterone has been implicated in promoting inflammatory and fibrotic pathways (Ma et al., 2020), whereas estrogen is thought to exert hepatoprotective effects by modulating oxidative stress and inflammatory cytokine production (Xu et al., 2022).

Earlier findings revealed that male mice exhibit lower worm burdens compared to females when infected with S. mansoni (Nakazawa et al., 1997). This difference has been linked to the presence of testosterone during early infection stages, suggesting hormonal influences on susceptibility. Testosterone administration to female mice prior to infection reduced worm burden, while castration of male mice increased the corresponding susceptibility, thus highlighting testosterone’s protective role during the early stages of infection (Nakazawa et al., 1997). Female mice infected with S. mansoni showed a stronger inflammatory response than male mice (Boissier et al., 2003). This suggests that host sex influences immune defense mechanisms during infection.

Liver fibrosis is a significant pathological consequence of S. mansoni infection, leading to severe complications such as portal hypertension and hepatosplenomegaly (Leite et al., 2013). Emerging evidence indicates that male hosts are prone to more severe hepatic fibrosis compared to females, likely driven by sex-specific differences in immune regulation and cytokine expression. A study examined cytokine patterns in schistosomiasis patients with Symmers’ fibrosis (Silva-Teixeira et al., 2004). The findings revealed that male patients with severe fibrosis exhibited significantly higher serum levels of interleukin-4 (IL-4), IL-5, and tumor necrosis factor-alpha (TNF-α) compared to females with similar fibrosis grades. The Th2 cytokines IL-4 and IL-5 as well as TNFα frequently promote fibrogenic signaling pathways indirectly by inducing alternative macrophage activation (M2 macrophages), thereby enhancing the activation and proliferation of hepatic stellate cells (HSCs) and augmenting their collagen synthesis. These cytokines are known to stimulate collagen synthesis, suggesting their involvement in fibrosis development especially in male patients. In our experiments, the two most abundant fibrillar collagens in S. mansoni–infected mice were type I and type III collagen, with the highest levels observed in mice infected at 14 weeks of age. Morphometric quantification of the Sirius red-stained areas also showed an accumulation of fibrillary collagen in liver tissue of infected black six mice (Müller et al., 2024). In contrast, female patients with intense fibrosis had lower levels of these profibrotic cytokines, indicating that other mediators may contribute to fibrosis in females (Silva-Teixeira et al., 2004). Epidemiological evidence clearly demonstrates that men exhibit a higher incidence of liver cirrhosis and hepatocellular carcinoma than women (Tapper and Parikh, 2018). A Canadian research group has hypothesized that biological sex influences the responsiveness of hepatic myeloid cells, thereby predisposing men to more severe hepatic inflammation (Kuipery et al., 2022). In particular, hepatic immune cells such as monocytes exhibit an increased pro-inflammatory potential upon activation. This heightened inflammatory response may help explain the elevated risk observed in men for developing liver cirrhosis and, consequently, hepatocellular carcinoma.

Deregulation of hepatic carbohydrate and lipid metabolism during Schistosomiasis is independent of host sex The liver is one of the primary organs targeted by S. mansoni, where parasite eggs induce chronic inflammation, fibrosis, and metabolic dysfunction. As the infection progresses, these pathological changes disrupt key hepatic processes, including glucose and lipid metabolism, amino acid synthesis, and bile acid homeostasis. These metabolic disturbances are not only central to the disease’s pathogenesis but also contribute substantially to the progression of liver-related complications such as portal hypertension, hepatomegaly, and hepatic fibrosis (Bülow et al., 2023; Buonfrate et al., 2025). A recent study examined the liver proteome of S. mansoni-infected hamsters and compared male and female host responses (Ghezellou et al., 2024). Egg deposition by S. mansoni was associated with a downregulation of hepatic proteins involved in energy production and metabolic pathways (Ghezellou et al., 2024). Our working group provided detailed information about the regulation of hepatic carbohydrate and lipid metabolism in female hamsters infected with S. mansoni (Bülow et al., 2023). Key enzymes of hepatic carbohydrate and lipid metabolism were regulated comparably in female and male hamsters infected with S. mansoni (Figure 2).

The hepatic expression of pyruvate kinase M2 (PKM2) and glucose-6-phosphate dehydrogenase (G6PD) was significantly elevated in male bisex-infected hamsters (Figure 2A), mirroring the regulation seen in female hamsters (Bülow et al., 2023). A similar upregulation of glycolysis-associated genes, including PKM2, has been observed in Schistosoma japonicum-infected female mice (Xu et al., 2019). G6PD, crucial for NADPH production, supports fatty acid synthesis and oxidative stress defense (Yang et al., 2019). Given that S. mansoni suppresses fatty acid synthesis, increased G6PD may help maintaining NADPH levels for glutathione synthesis (Salvemini et al., 1999), which has been shown to reduce schistosome-induced oxidative stress in hepatocytes (Bülow et al., 2023). Furthermore, glycogen synthase expression was reduced in male bisex-infected hamsters (Figure 2B), consistent with female (Bülow et al., 2023) hamsters, while gluconeogenesis enzyme PCK2 expression remained unchanged (Figure 2B) (Bülow et al., 2023). Similarly, fatty acid synthase (FAS), acetyl-CoA carboxylase 1 (ACC1), and acetyl-CoA synthetase (ACS) were downregulated in male (Figure 2C) and female (Bülow et al., 2023) hamsters, reflecting metabolic suppression seen in S. japonicum infection.

Schistosome eggs appear to drive a glycolytic metabolic program that enables rapid ATP production in the cytosol under hypoxic conditions, accompanied by a concurrent reduction in oxidative phosphorylation (OXPHOS), the mitochondrial pathway responsible for oxygen-dependent ATP generation. The cells underwent a metabolic reprogramming characterized by a transition from OXPHOS-dependent mitochondrial respiration to a glycolytic metabolic state. These results suggest that schistosome eggs reprogram parts of the host hepatic metabolism by enhancing catabolic pathways such as glycolysis while suppressing anabolic processes such as glycogen synthesis, gluconeogenesis, and fatty acid synthesis. Furthermore, we have previously demonstrated, that S. mansoni infection led to hepatic depletion of neutral lipids and glycogen, with schistosome eggs mobilizing and storing host-derived lipids (Bülow et al., 2023). Metabolic disruptions in xenobiotic processing, energy metabolism, and lipid homeostasis were observed without clear sex-dependent differences (Ghezellou et al., 2024). Figure 2D summarizes the regulatory mechanisms affecting hepatic carbohydrate and lipid metabolism during S. mansoni infection from our research and published studies. The direction of regulation of key enzymes involved in hepatic metabolism of bisex-infected animals or hepatocytes in vitro stimulated with egg-derived antigens (SEA) is detailed in Table 1. Increasing evidence indicates that mitochondrial phenotypes differ between males and females in the liver, with important implications for inflammatory susceptibility and disease progression. Female hepatic cells generally exhibit a more oxidative, OXPHOS-oriented mitochondrial metabolism characterized by greater respiratory efficiency and enhanced resistance to oxidative stress. In contrast, male liver cells appear more prone to inflammation-associated metabolic reprogramming toward glycolysis, particularly under conditions of chronic immune activation (Chen J. et al., 2025). These sex-specific differences are thought to be driven, at least in part, by hormone-dependent regulation of mitochondrial function and antioxidant capacity within the hepatic microenvironment. Such divergent mitochondrial phenotypes may contribute to the heightened inflammatory tone observed in male livers and thereby increase susceptibility to progressive liver inflammation, fibrosis, and subsequent disease severity (Nadal-Casellas et al., 2010).

Male ApoE^−/− mice are widely used as a model of dysregulated lipid metabolism and chronic inflammation, providing a valuable tool to study the interplay between metabolic imbalance, immune activation, and liver pathology (Lo Sasso et al., 2016). Schistosomiasis has been shown to protect male ApoE^−/− mice from the development of atherosclerosis, diabetes and obesity while altering the metabolism of liver macrophages. In the study mentioned the authors found that macrophages generated from bone marrow myeloid progenitors from infected male mice have long-lived increases in their basal metabolism of lipids. Their results suggest that metabolic reprogramming is long-lasting without exposure to active infection, and develops a memory-like phenotype in myeloid cells. This reprogramming was transferrable via bone marrow transplantation. Under nutrient deprivation, hepatocytes shift their metabolism into a survival mode: glucose is supplied via glycogenolysis and gluconeogenesis, lipid stores are increasingly oxidized, and amino acids are mobilized for energy production (Rui, 2014). Concurrently, energy-consuming processes are downregulated, autophagy is activated, and antioxidant defenses are mobilized to preserve cellular integrity (Byrnes et al., 2022). Novaes et al. recently demonstrated that progressive liver fibrosis, sustained high levels of reactive oxygen species (ROS), pronounced DNA damage, and a reduction in p16 and p21 expression are associated with impaired hepatocyte proliferation during the chronic phase of S. mansoni infection. Consequently, pharmacological inhibition of both the infection and granulomatous inflammation is crucial to prevent these indicators of premature senescence linked to hepatocyte replication deficits and to promote liver regeneration in Schistosoma mansoni infection (Novaes et al., 2025).

Amer et al. also pointed out that schistosome infection in mouse models leads to an increase in Th2 and regulatory T cell cytokines (Amer et al., 2023). In addition, changes in the lipid profile and blood sugar levels were observed in infected diabetic and obese animals. Surprisingly, schistosome infection had a positive effect on insulin levels in obese mice. T2DM and obesity, however, increased tissue egg counts and fibrosis, while the infection enhanced lipid profiles and insulin sensitivity in obese mice (Amer et al., 2023). These conditions contribute to a specific hepatic microenvironment which affects mitochondrial function. Mitochondria are energy producers in cells and are responsible for maintaining normal functions by controlling mitochondrial redox homeostasis, metabolism, bioenergetics, and cell death pathways (Chen T.-H. et al., 2025).